For advanced cases in stage III and stage IV of head and neck squamous cell carcinomas, triple combination therapy comprising surgery, radiation, and chemotherapy is performed as a rule. With respect to surgical treatment, autologous tissue transplantation of free flaps, intestine, and bone with vascular stalk became popular particularly after the last half of the 1980s, which made extended resection relatively easy procedure and also provided specific effects on maintenance of functions and morphology, resulting in remarkable improvement of local control (Non-patent Document 1). Even absolute resection of cancers infiltrating the internal carotid artery or skull base became possible (Non-patent Document 2 and Non-patent Document 3). However, in the case of the extended range of resection, functional and morphological retention by reconstructive surgery are limited, and remarkable deterioration of the QOL of patients is caused. Further, in stage IV, a combination of radiation and chemotherapy is indispensable to improve therapeutic outcomes; however, in stage IV, for N2c and N3 cases and cases of infiltration in the carotid artery, therapeutic outcomes were poor even with extended resection, and the 5-year survival rate was lower than 50% (Non-patent Document 4). In a treatment comprising extended resection followed by a combination of radiation and chemotherapy, the survival rate improved significantly, but functional preservation for the larynx and the like was difficult.
Meanwhile, in Japan, since the launch of a platinum preparation in 1985, the preparation has been used as a neo-adjuvant or adjuvant therapy with the expectation for high efficacy of chemotherapy (Non-patent Document 5 and Non-patent Document 6). However, randomized studies in Europe and the US have almost resulted in conclusion by about 10 years previously that neo-adjuvant treatment does not contribute to the improvement in survival rate, compared with radiation monotherapy, though it is somewhat effective for functional preservation (Non-patent Document 7). At present, concurrent combination therapy comprising radiation therapy and chemotherapy is attracting attention as the central treatment for triple combination therapy, and randomized studies have reported that this therapy is more likely to achieve functional retention than radiation monotherapy, and also contributes to an improvement in survival rate (Non-patent Document 8). However, the improvement in survival rate is up to 0 to 8% and the 5 years survival rate is about 20 to 40%; moreover, many studies have excluded N2c, N3, or advanced T4 cases from the study populations. Additionally, the results of salvage surgery are poor (Non-patent Document 9).
Thus, the treatment of advanced head and neck squamous cell carcinomas, whether by surgery, radiation, or chemotherapy, poses major problems. To improve the results, and to lessen the burden on patients, a new therapeutic strategy is indispensable (Non-patent Document 10).
Natural killer T cells (NKT cells) are unique cells expressing both a T cell receptor (TCR) and a natural killer cell receptor (NKR) on the same cell surface, and were first reported as the fourth lymphocytes distinct from T cells, B cells, and natural killer cells (NK cells) (Non-patent Document 11, Non-patent Document 12, and Non-patent Document 13). The TCR on NKT cells is composed of an extremely limited α chain (Vα14-Jα281 in mice and Vα24-JαQ in humans) and β chain (Vβ8, Vβ7, or Vβ2 in mice and Vβ11 in humans) (Non-patent Document 14, Non-patent Document 15, Non-patent Document 16, Non-patent Document 17, and Non-patent Document 18), and it has been revealed that a molecule recognized thereby is a CD1d molecule, which is an antigen presenting molecule similar to major histocompatibility complex (MHC) Class I (Non-patent Document 19 and Non-patent Document 20). Recently, it was shown that the presentation of α-galactosylceramide, one of glycolipids, on CD1d could specifically activate NKT cells (Non-patent Document 21 and Non-patent Document 22). NKT cells activated with a ligand produce a large amount of interferon γ (IFN-γ) and interleukin-4 (IL-4) and exhibit potent cytotoxic activity via perforin/granzyme B. NKT cells activated with a ligand were thereafter clarified to have a unique action mechanism where various immune reactions are induced, and as a result, a strong anti-tumor action is exhibited. It has been reported that in various liver metastasis models of mice, α-galactosylceramide exhibited a remarkable anti-tumor effect that depends on NKT cells (Non-patent Document 23, Non-patent Document 24, and Non-patent Document 25). It was also found that α-galactosylceramide can specifically activate not only mouse NKT cells but also human NKT cells (Non-patent Document 26). Based on these results, a phase I clinical study with administration of α-galactosylceramide directed to patients with solid cancers has been performed in the Netherlands (Non-patent Document 27). Further, a lung cancer therapy involving infusion of NKT cells activated with α-galactosylceramide has been conducted, but no clear effect on tumor regression has been observed (Non-patent Document 28).
Dendritic cells (DCs) are the most potent antigen presenting cells in a T cell-dependent immune response. In cancer patients, it is said that DCs are inhibited in their maturation, activation, and mobilization by interleukin-10 (IL-10), vascular endothelial growth factor (VEGF) and the like that are secreted from tumors. Meanwhile, DCs are expected to overcome the above-mentioned condition where in vivo maturation and activation of DCs are suppressed and to serve an effective treatment, when taking out DC precursors from the body, leading them to a maturation process, further pulsing them with a tumor-specific antigen to impart a tumor antigen-specific immuno-reactivity, and then retransfusing the cells into the cancer patient. Clinical studies of a cancer vaccine therapy with DCs (DC therapy) have already started for malignant lymphoma, malignant melanoma, multiple myeloma, prostate cancer, renal cell carcinoma, and the like, and it has been preliminary reported that induction of antigen-specific cytotoxic T cells (CTLs) and tumor regression effects were observed. Reported adverse effects associated with the DC therapy include chill, fever, and the like. Development of autoantibodies (anti-thyroid antibody and the like) and having onset of chronic rheumatoid arthritis have been reported worldwide as adverse effects, but other severe adverse effects and complications have not been reported. Thus, the DC therapy is thought to be a relatively safe treatment method. However, general DC therapies utilizing tumor-specific molecules have such problems that their effect is expected only on the limited kind of tumors because of the specificity, and that tumor cells inpatients having different MHC or having reduced expression of MHC class I could not be targeted by CTL, because of MHC restriction.
Meanwhile, the above-mentioned anti-tumor action mechanism of α-galactosylceramide led to such an expectation that an anti-tumor effect should be obtained by transferring α-galactosylceramide-pulsed DCs into cancer-bearing mice. The results of examinations using animals showed that delayed timing of α-galactosylceramide administration in a malignant tumor metastasis model resulted in disappearance of the metastasis suppressing effect, whereas administration of α-galactosylceramide-pulsed DCs to cancer-bearing mice resulted in almost complete suppression of a lung or liver metastasis even when the timing of administration was delayed to some extent (Non-patent Document 29). This suggests that the administration of α-galactosylceramide in the form of being presented on DCs is more preferable than the administration of α-galactosylceramide itself in order to achieve efficient activation of NKT cells in vivo. Besides, since a CD1d molecule-NKT cell antigen receptor system utilized in this treatment method is common in all humans, NKT cells of anyone may be activated with α-galactosylceramide. Further, since activated NKT cells exhibit cytotoxic activity regardless of the expression of a MHC class I molecule, it is conceivable that the treatment method should have an advantage of complementing drawbacks of such a DC therapy as pulsing a cancer-specific peptide.
The safety trial of “treatment method using α-galactosylceramide (KRN 7000)-pulsed cells directed to lung cancer recurrent cases and patients with advanced lung cancer” approved by Ethics Committee of Chiba University revealed that an α-galactosylceramide-pulsed dendritic cell therapy may be performed safely. Further, the safety test of “clinical study using activated NKT cells directed to lung cancer recurrent cases and cases with advanced lung cancer” revealed that the intravenous administration of the activated NKT cells may be performed safely.
The intravenous administration of α-galactosylceramide-pulsed dendritic cells has been hitherto examined mainly for recurrent cases of lung cancer. The phase I study was conducted with escalation of the number of transferring cells from 5×107/m2 at level 1 to 2.5×108/m2 at level 2 and 1×109/m2 at level 3. As a result, an increase in peripheral blood NKT cells was observed in one case out of total 11 cases participated in this study, where the cells at the number of level 3 was administered (Non-patent Document 30). However, α-galactosylceramide-pulsed dendritic cells at the number of level 1 and level 2 did not provided such an immune response where NKT cells increase in peripheral blood.
As described above, the administration of antigen presenting cells pulsed with an NKT cell ligand such as α-galactosylceramide can more efficiently stimulate NKT cells, stimulate an immunity, and treat diseases such as tumors, as compared to the in vivo direct administration of the NKT cell ligand.
The inventors of the present invention have reported that when dendritic cells pulsed with an antigen were administered through the nasal mucosa, the dendritic cells migrated the cervical lymph node highly selectively. The inventors have also confirmed that NKT cells were not detected in the normal non-metastatic cervical lymph node, while numerous NKT cells were detected in the cervical lymph node with metastasized head and neck cancer (Non-patent Document 31 and Non-patent Document 32).
Further, the inventors of the present invention have found that the administration of NKT cell ligand-pulsed antigen presenting cells through the upper respiratory tract mucous membrane induces NKT cells selectively in the cervical lymph node while NKT cells are usually not present in the cervical lymph node. The inventors have also found that the use of the administration method allows efficient stimulation of NKT cells with very small amount of antigen presenting cells also in tissues (such as peripheral blood) other than the cervical lymph node, and stimulation of a systemic immune response (Patent Document 1).
As described above, a cellular immunotherapy of cancer has been developed by utilizing, for example, cells having an anti-tumor activity or antigen presenting cells for activating cells capable of exhibiting an anti-tumor activity.
Meanwhile, in treatment of cancer, the selective intraarterial infusion of an anti-cancer drug has been widely used in a standard treatment. The selective intraarterial infusion therapy is a treatment method involving administering an anti-cancer drug directly into the tumor nutrient blood vessel, and thereby allowing a high concentration of a medicament to be distributed to a tumor, to enhance an anti-tumor effect and enhance a therapeutic effect, and to reduce a medicament circulating throughout the body to alleviate adverse effects. Also in head and neck cancer, a selective intraarterial infusion therapy of an anti-cancer drug has been developed, and there is a report that this therapy showed low improvement rate of the survival rate in the case of using the therapy alone, but improved a survival rate as well as a local control rate in a combination therapy with radiotherapy (Non-patent Document 33).
However, it has not been known whether the intraarterial administration of activated cells having an anti-tumor activity to the tumor nutrient blood vessel can efficiently deliver those cells to tumor tissues, and whether the administration can provoke a stronger anti-tumor reaction.
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7(7):1157-61    Non-patent Document 17: Taniguchi M et al., “Essential requirement of an invariant V alpha 14 T cell antigen receptor expression in the development of natural killer T cells”, Proc Natl Acad Sci USA 1996 Oct. 1; 93(20):11025-8    Non-patent Document 18: Makino Y et al., “Development of V alpha 4+ NKT cells in the early stages of embryogenesis”, Proc Natl Acad Sci USA 1996 Jun. 25; 93(13):6516-20    Non-patent Document 19: Bendelac A et al. , “CD1 recognition by mouse NK1+ T lymphocytes”, Science 1995 May 12; 268(5212):863-5    Non-patent Document 20: Adachi Y et al., “Positive selection of invariant V alpha 14+ T cells by non-major histocompatibility complex-encoded class I-like molecules expressed on bone marrow-derived cells”, Proc Natl Acad Sci USA 1995 Feb. 14; 92(4):1200-4    Non-patent Document 21: Kawano T et al., “CD1d-restricted and TCR-mediated activation of V alpha 14 NKT cells by glycosylceramides”, Science 1997 Nov. 28; 278(5343):1626-9    Non-patent Document 22: Cui J et al., “Requirement for V alpha 14 NKT cells in IL-12-mediated rejection of tumors”, Science 1997 Nov. 28; 278(5343):1623-6    Non-patent Document 23: Morita M, Motoki K, Akimoto K, Natori T, Sakai T, Sawa E, Yamaji K, Koezuka Y, Kobayashi E, Fukushima H., “Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice”, J Med Chem 1995 Jun. 9; 38(12):2176-87    Non-patent Document 24: Nakagawa R et al., “Treatment of hepatic metastasis of the colon 26 adenocarcinoma with an alpha-galactosylceramide, KRN7000”, Cancer Res 1998 Mar. 15; 58(6):1202-7    Non-patent Document 25: Kawano T et al., “Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated V alpha 14 NKT cells”, Proc Natl Acad Sci USA 1998 May 12; 95 (10):5690-3    Non-patent Document 26: Kawano T et al., “Antitumor cytotoxicity mediated by ligand-activated human V alpha 24 NKT cells”, Cancer Res 1999 Oct. 15; 59(20):5102-5    Non-patent Document 27: Giaccone G et al., “A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) inpatients with solid tumors”, Clin Cancer Res 2002 December; 8(12);3702-9    Non-patent Document 28: Motohashi S et al., “A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer”, Clin Cancer Res. 2006 Oct. 15; 12(20):6079-86    Non-patent Document 29: Toura I et al., “Cutting edge: inhibition of experimental tumor metastasis by dendritic cells pulsed with alpha-galactosylceramide”, J Immunol 1999 Sep. 1; 163(5):2387-91    Non-patent Document 30: Ishikawa A et al., “A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 2005 Mar. 1; 11(5):1910-7    Non-patent Document 31: Horiguchi Shigetoshi et al., “In vivo migration of nasal mucosal dendritic cells”, Journal of Japan society of Immunology & Allergology in Otolaryngology, 2003 21(2):10-11    Non-patent Document 32: Okamoto Yoshitaka et al., “Cellular immunotherapy and heavy particle therapy introduced for pharyngeal cancer”, Chiba University COE report, 2005:116-118    Non-patent Document 33: Fuwa N et al., “A combination therapy of continuous superselective intraarterial carboplatin infusion and radiation therapy for locally advanced head and neck carcinoma”, Cancer 2000 Nov. 15; 89(10):2099-105